Safety, PK and Efficacy of ONC-392 in Monotherapy and in Combination of Anti-PD-1 in Advanced Solid Tumors and NSCLC

Ovarian Cancer Clinical Trial

— PRESERVE-001  

Official title:

Safety, Pharmacokinetics (PK), and Efficacy of ONC-392 as a Single Agent and in Combination With Pembrolizumab in Advanced Solid Tumors and NSCLC: An Open Label Phase IA/IB Study. Preserve CTLA4 Checkpoint Function (PRESERVE-001)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04140526
• Other study ID #: ONC-392-001
• Secondary ID: 4R44CA250824-022
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: September 16, 2020
• Est. completion date: December 31, 2024

Study information

• Verified date: January 2024
• Source: OncoC4, Inc.
• Contact: Pan Zheng, MD, PhD
• Phone: 202 751 6823
• Email: pzheng[@]oncoc4.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a First-in-Human Phase IA/IB/II open label dose escalation study of intravenous (IV) administration of ONC-392, a humanized anti-CTLA4 IgG1 monoclonal antibody, as single agent and in combination with pembrolizumab in participants with advanced or metastatic solid tumors and non-small cell lung cancers.

Description:

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), also known as CD152 (cluster of differentiation 152), is a cell surface protein receptor that interacts with B7-1 (CD80) and B7-2 (CD86) to ensure proper function of regulatory T cells and protect host against autoinflammatory diseases. Anti-CTLA-4 monoclonal antibodies (mAbs) have demonstrated strong and broad cancer immunotherapeutic effects (CITE) in a variety of preclinical models and are used clinically both as monotherapy and as part of combination therapy with Nivolumab (anti-PD-1). However, CTLA-4 monotherapy has more immunotherapy-related adverse effects (irAEs) than anti-PD-1/PD-L1 therapy. In addition, the rate of severe irAE (Grades 3 and 4) reached 55% in melanoma patients receiving combination of Ipilimumab and Nivolumab. The strong irAEs further limit the doses tolerated by cancer patients. Nevertheless, combination with anti-PD-1 resulted in significantly improved response rates and patient survival in multiple types of cancer. Furthermore, anti-CTLA-4 antibodies induce long-lasting immunity in cancer patients. Therefore, CTLA-4 remains an important immunotherapy target, but major challenges remain in improving both safety and efficacy of anti-CTLA-4 mAbs. ONC-392 is a highly selective, humanized monoclonal IgG1-kappa isotype antibody against CTLA-4. The parental clone was identified through in vivo screening in humanized CTLA-4 mouse model for high anti-tumor efficacy and low autoimmune toxicity. We have recently demonstrated that ONC-392 is dissociation from CTLA-4 under low pH to allow its escape from lysosomal degradation and recycle to cell surface. We have provided several lines of evidence for the notion that a pH-sensitive antibody ONC-392 is not only safer but also more effective in Treg depletion and tumor rejection than the Ipilimumab, which is pH-insensitive. First, by preserving CTLA-4 on the cell surface, Onc-392 leaves higher ligand density for better ADCC. Second, Onc-392 is more efficient in Treg depletion in tumor microenvironment. Third, Onc-392 is significantly more potent in inducing rejection of large tumors. The study consists of four parts: (1) The Part A study is a dose-finding rapid titration, Phase I trial of ONC-392 as a single agent in patients with advanced or metastatic solid tumors with various histology. The aim of this trial is to define the recommended Phase II dose for ONC-392 monotherapy (RP2D-M). (2) The Part B study is a dose-finding phase with ONC-392 in combination with a standard dose of 200 mg pembrolizumab in patients with advanced or metastatic solid tumors. (3) The Part C consists of different expansion arms. 1. Arm A: Pancreatic Cancer Cohort, ONC-392 monotherapy, will enroll advanced/metastatic pancreatic cancer patients who have progressive disease after first and second lines of systemic treatment. 2. Arm B: TNBC Cohort, ONC-392 monotherapy, will enroll advanced/metastatic TNBC patients who have progressive disease after prior systemic treatments, including checkpoint inhibitor immunotherapy. 3. Arm C: NSCLC Mono Cohort 1, ONC-392 monotherapy, will enroll advanced/metastatic NSCLC patients with EGFR or ALK mutations who have progressive disease after prior systemic treatments, including targeted therapy or checkpoint inhibitors. 4. Arm D: NSCLC IO Naïve Cohort, ONC-392/Pembrolizumab combination therapy, will enroll advanced/metastatic NSCLC cancer patients who are treatment naïve, or anti PD (L)1 immunotherapy naïve and PD-L1-positive (PD L1 TPS ≥ 1%). 5. Arm E: NSCLC IO R/R Cohort, ONC-392/Pembrolizumab combination therapy, will enroll advanced/metastatic NSCLC cancer patients who are R/R to prior anti-PD-(L)1 immunotherapy regardless of PD-L1 status. 6. Arm F: Melanoma IO Naïve Cohort, ONC-392/Pembrolizumab combination therapy, will enroll advanced/metastatic Melanoma patients who are treatment naïve, or checkpoint inhibitor immunotherapy naive. Prior systemic chemotherapy or targeted therapy are allowed. 7. Arm G: Melanoma IO R/R Cohort, ONC-392/Pembrolizumab combination therapy, will enroll advanced/metastatic melanoma patients who are R/R to anti-PD-(L)1 immunotherapy. 8. Arm I: NSCLC Mono Cohort 2, ONC-392 monotherapy, will enroll advanced/metastatic NSCLC patients without EGFR or ALK mutations who have progressive disease after prior systemic treatments, including chemotherapy or checkpoint inhibitors. Patient must have anti-PD-(L)1 treatment, either alone or in combination, as last treatment before enrollment. Prior anti-CTLA-4 treatment is allowed. 9. Arm J: Melanoma Mono Cohort, ONC-392 monotherapy, will enroll advanced/metastatic melanoma patients who are R/R to anti-PD-(L)1 immunotherapy. 10. Arm K: Head and Neck Squamous Cell Carcinoma (HNSCC), ONC-392 monotherapy, will enroll advanced/metastatic HNSCC patients with or without positive HPV who have progressive disease after prior systemic treatments, including chemotherapy or checkpoint inhibitors. Patient must have anti-PD-(L)1 treatment, either alone or in combination, as last treatment before enrollment. 11. Arm L: Ovarian Cancer, ONC-392 monotherapy, will enroll patients with advanced/metastatic ovarian cancer who have progressive disease after prior systemic treatments, including chemotherapy, targeted therapy or checkpoint inhibitors. 12. Arm M: Solid Tumors, ONC-392 monotherapy, will enroll patients with advanced/metastatic solid tumors who are not eligible for Arm A-C or H-L, who have progressive disease after prior systemic treatments, including chemotherapy, targeted therapy or checkpoint inhibitors. 13. Arm N: Renal Cell Carcinoma, ONC-392 monotherapy, will enroll advanced/metastatic RCC patients who are R/R to anti-PD-(L)1 immunotherapy. (4) Part D is a Phase II study in recurrent and/or metastatic adenoid cystic carcinoma with ONC-392 monotherapy.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 914
• Est. completion date: December 31, 2024
• Est. primary completion date: June 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. . Patients must have a histological or cytological diagnosis of NSCLC or any other type of carcinoma or sarcomas, progressive metastatic disease, or progressive locally advanced disease not amenable to local therapy.

1. In the Part A Phase I dose escalation study of ONC-392 monotherapy, patients with advanced/metastatic solid tumors of any histology are eligible for participation. Please note: tumor types of primary interest in this study are malignant melanoma, renal cell carcinoma, hepatocellular carcinoma, non-small cell lung cancer, head and neck carcinoma, gastric carcinoma, ovarian carcinoma, colorectal cancer, any type of sarcoma.

2. In Part B dose finding of the ONC-392 plus pembrolizumab combination, patients with advanced/metastatic solid tumors of any histology that Pembrolizumab has been approval as standard of care are eligible for participation.

3. In Part C, patients with pancreatic cancer, triple negative breast cancer, non small cell lung cancer, melanoma, Head and Neck cancer, ovarian cancer, and other solid tumors are eligible.

4. In Part D, patients with recurrent and/or metastatic adenoid cystic carcinoma with disease progression within 12 months are eligible.

5. Patients must have RECIST V1.1 Measurable disease:

2. Patient is male or female and >18 years of age on day of signing informed consent.

3. Patient must have a performance status of 0 or 1 on the ECOG Performance Scale

4. Patient must have adequate organ function as indicated by the following laboratory values: Hematological: Absolute neutrophil count (ANC) =1,500 /mcL; Plateletsa =100,000 / mcL; Hemoglobin =9 g/dL or =5.6 mmol/L- without qualifications; Renal: Serum creatinine =1.5 X upper limit of normal (ULN); Hepatic: Serum total bilirubin =1.5 X ULN; OR Direct bilirubin = ULN for patients with total bilirubin levels >1.5 ULN; AST (SGOT) and ALT (SGPT) =2.5 X ULN, OR =5 X ULN for patients with active liver metastases Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) =1.5 X ULN Activated Partial Thromboplastin Time (aPTT) =1.5 X ULN

5. Patient has voluntarily agreed to participate by giving written informed consent.

6. Female patient of childbearing potential has a negative urine or serum pregnancy test.

7. Female and Male patients must agree to use adequate methods of contraception starting with the first dose of study drug through 90 days after the last dose of study therapy. Exclusion Criteria: A patient meeting any of the following criteria is not eligible to participate in this

study:

1. Patients who have not recovered to CTCAE = 1 from the AE due to cancer therapeutics. The washout period for cancer therapeutic drugs (such as chemotherapy, radioactive, or targeted therapy) is 21 days, and for antibody drug 28 days.

2. Patients who are currently enrolled in a clinical trial of an investigational agent or device.

3. Patients who are on chronic systemic steroid therapy at doses >10 mg/day

4. Patients who have active symptomatic brain metastasis or leptomeningeal metastasis.

5. Patients who have an active infection requiring systemic IV therapy within 14 days of prior to administration of ONC-392 or combined ONC-392 and Pembrolizumab.

6. Patients who have a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator.

7. Patients with known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

8. Patients who are pregnant or breastfeeding.

9. For the Part B and Part C Arm D to G, the patients that are deemed to be not suitable for Pembrolizumab.

Related Conditions & MeSH terms

• Adenoid Cystic Carcinoma
• Advanced Solid Tumor
• Carcinoma
• Carcinoma, Adenoid Cystic
• Cervical Cancer
• Esophageal Cancer
• Gastric Cancer
• Gastroesophageal Junction Adenocarcinoma
• Lung Neoplasms
• Metastatic Breast Cancer
• Metastatic Colorectal Cancer
• Metastatic Head and Neck Carcinoma
• Metastatic Melanoma
• Metastatic Prostate Cancer
• Metastatic Renal Cell Carcinoma
• Non Small Cell Lung Cancer
• Ovarian Cancer
• Pancreas Cancer
• Pancreatic Neoplasms
• Salivary Gland Cancer
• Salivary Gland Neoplasms
• Sarcomas
• Small Cell Lung Cancer
• Small Cell Lung Carcinoma
• Urothelial Carcinoma

Intervention

Drug:
• ONC-392
ONC-392 will be given by intravenous infusion, once every 21 days (Q3W). In Part C Arm M and in Part D, ONC-392 will be given Q4W.
• Pembrolizumab
Pembrolizumab will be given intravenous (IV) infusion at 200 mg/cycle, once every 21 days (Q3W).

Locations

Country	Name	City	State
Australia	Cancer Research SA	Adelaide	South Australia
Australia	Southern Oncology Clinical Research Unit	Bedford Park	South Australia
Australia	Newcastle Private Hospital	New Lambton Heights	New South Wales
Australia	Tasman Oncology Research	Southport	Queensland
United States	University of Michigan Medical Center	Ann Arbor	Michigan
United States	Emory University Winship Cancer Institute	Atlanta	Georgia
United States	Florida Cancer Specialists	Atlantis	Florida
United States	University of Colorado Hospital	Aurora	Colorado
United States	Greater Baltimore Medical Center	Baltimore	Maryland
United States	The Center for Cancer and Blood Disorders	Bethesda	Maryland
United States	Dana Farber Cancer Institute	Boston	Massachusetts
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Tennessee Oncology Chattanooga Memorial Plaza	Chattanooga	Tennessee
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	The Ohio State University James Cancer Center	Columbus	Ohio
United States	Zangmeister Cancer Center	Columbus	Ohio
United States	University of California at Davis	Davis	California
United States	The Oncology Institute of Hope and Innovation	Downey	California
United States	City of Hope Cancer Center	Duarte	California
United States	NEXT/Virginia Cancer Specialists	Fairfax	Virginia
United States	University of Connecticut Medical Center	Farmington	Connecticut
United States	University of Florida Health Cancer Center	Gainesville	Florida
United States	Pennsylvania Cancer Specialists & Research Institute (Formerly Gettysburg Cancer Center)	Gettysburg	Pennsylvania
United States	Prisma Health	Greenville	South Carolina
United States	Penn State Cancer Institute	Hershey	Pennsylvania
United States	Houston Methodist Cancer Center	Houston	Texas
United States	Oncology Consultants	Houston	Texas
United States	Norton Health	Lexington	Kentucky
United States	Atlantic Healthcare System	Morristown	New Jersey
United States	Tennessee Oncology - Nashville	Nashville	Tennessee
United States	Memorial Sloan Kettering Cancer Center	New York	New York
United States	Nuvance Health	Norwalk	Connecticut
United States	Ocala Oncology Florida Cancer Affiliates	Ocala	Florida
United States	AdventHealth Cancer Institute	Orlando	Florida
United States	Memorial Cancer Institute	Pembroke Pines	Florida
United States	University of Utah Huntsman Cancer Institute	Salt Lake City	Utah
United States	University of Washington / Fred Hutchinson Cancer Center	Seattle	Washington
United States	Highlands Oncology Group	Springdale	Arkansas
United States	MedStar Georgetown University Hospital	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
OncoC4, Inc.	National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia, 

References & Publications (6)

Du X, Liu M, Su J, Zhang P, Tang F, Ye P, Devenport M, Wang X, Zhang Y, Liu Y, Zheng P. Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice. Cell Res. 2018 Apr;28(4):433-447. doi: 10.1038/s41422-018-0012-z. Epub 2018 Feb 20. — View Citation

Du X, Tang F, Liu M, Su J, Zhang Y, Wu W, Devenport M, Lazarski CA, Zhang P, Wang X, Ye P, Wang C, Hwang E, Zhu T, Xu T, Zheng P, Liu Y. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res. 2018 Apr;28(4):416-432. doi: 10.1038/s41422-018-0011-0. Epub 2018 Feb 22. — View Citation

Liu Y, Zheng P. Preserving the CTLA-4 Checkpoint for Safer and More Effective Cancer Immunotherapy. Trends Pharmacol Sci. 2020 Jan;41(1):4-12. doi: 10.1016/j.tips.2019.11.003. Epub 2019 Dec 10. — View Citation

Lute KD, May KF Jr, Lu P, Zhang H, Kocak E, Mosinger B, Wolford C, Phillips G, Caligiuri MA, Zheng P, Liu Y. Human CTLA4 knock-in mice unravel the quantitative link between tumor immunity and autoimmunity induced by anti-CTLA-4 antibodies. Blood. 2005 Nov 1;106(9):3127-33. doi: 10.1182/blood-2005-06-2298. Epub 2005 Jul 21. — View Citation

May KF Jr, Roychowdhury S, Bhatt D, Kocak E, Bai XF, Liu JQ, Ferketich AK, Martin EW Jr, Caligiuri MA, Zheng P, Liu Y. Anti-human CTLA-4 monoclonal antibody promotes T-cell expansion and immunity in a hu-PBL-SCID model: a new method for preclinical screening of costimulatory monoclonal antibodies. Blood. 2005 Feb 1;105(3):1114-20. doi: 10.1182/blood-2004-07-2561. Epub 2004 Oct 14. — View Citation

Zhang Y, Du X, Liu M, Tang F, Zhang P, Ai C, Fields JK, Sundberg EJ, Latinovic OS, Devenport M, Zheng P, Liu Y. Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Cell Res. 2019 Aug;29(8):609-627. doi: 10.1038/s41422-019-0184-1. Epub 2019 Jul 2. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Dose limiting toxicity (DLT) in monotherapy	The number of subjects who have dose limiting toxicity during the first cycle of study drug, ONC-392, administration.	21 days
Primary	Maximal tolerable dose (MTD) in monotherapy	The study drug, ONC-392, dose level that has two out of six subjects who have dose limiting toxicity.	21 days
Primary	Recommended Phase II Dose (RP2D)	The study drug, ONC-392, dose level that is one level below MTD, or an intermediate dose level that below MTD and pre-specified in protocol. This dose level will be the RP2D for monotherapy.	21 days
Primary	Rate of treatment related adverse events (TRAE) according to CTCAE v5.0	The safety profile will be presented as tabulated TRAE.	One year
Secondary	The serum half life of the study drug, ONC-392, in monotherapy.	To determine the drug concentration in serum samples that are taken in various timepoints during the treatment in order to calculate drug half life.	12 weeks
Secondary	The serum half life of the study drug, ONC-392, in combination therapy with Pembrolizumab.	To determine the drug concentration in serum samples that are taken in various timepoints during the treatment in order to calculate drug half life.	12 weeks
Secondary	Objective Response Rate (ORR)	To determine the objective response rate based on RECIST v1.1.	1 year
Secondary	Progression Free Survival (PFS)	To determine the progression free survival based on RECIST 1.1 and iRECIST.	1 year
Secondary	Overall Survival (OS)	To determine the overall survival.	1 year